1. Field of the Invention.
The present invention is concerned with a novel pharmaceutical use of the compound 1-[4-(4'-sulfanilyl)phenyl]urea, and derivatives thereof, including the novel ureidosulfones, 1-[4-(4'-sulfanilyl)2-hydroxyphenyl]urea and 1-[4-(4'-sulfanilyl)3-hydroxyphenyl]urea, for its action in treating clinical manifestations associated with the genus Leishmania, resulting in the disorder known as leishmaniasis.
2. Description of the Prior Art.
Leishmaniasis is a debilitating condition caused by any of several species of Leishmania and transmitted by several phlebotomine sandflies. The manifestations may be visceral, mucocutaneous or cutaneous and the strain of the infecting organism and host's immunologic status can influence the clinical signs and symptoms of the parasitic disease. However, leishmaniasis remains a complex disease to treat since so many organ systems of the body can be affected including skin, liver, spleen and bone marrow and in spite of the extensive research which has been carried out in search of effective and well tolerated agents for treatment of its various causal agents and intermediate vectors, few such agents have been discovered. If left untreated, the fatality rate approaches 90%.
No identification of, or description of the utility of 1-[4-(4'-sulfanilyl)phenyl]urea or related ureido compounds for leishmaniasis has appeared, nor has any prediction been made previously as to the probability of the diarylsulfonyl ureas having use in the treatment of said disorders termed leishmaniasis. Based on the biological activities of 1-[4-(4'-sulfanilyl)phenyl]urea and a number of related compounds described by Shigeura et al [Biochemical Pharmacology, 24:687-691 (1975)], no effect was noted on the biosythesis of DNA, RNA or protein in cultured animal cells, but rather there was demonstrated a marked effect of the previously reported compounds on phosphatidylcholine synthesis. A similar effect was noted for the diaminodiphenylsulfone compound, 4,4'-diaminodiphenylsulfone, but only the ureido compound was substantially effective as an antiviral compound against Marek's disease (ref. U.S. Pat. No. 2,056,955), suggesting an anticipated differential profile of biological actions for diaminodiphenylsulfones as compared to the substituted ureas.
4,4'-diaminodiphenylsulfone is an established antimalarial and antileprotic agent but the corresponding ureido compound, identified for its activity against coccidial infection (U.S. Pat. No. 2,328,548) has not to date proven commecially useful as a pharmaceutical against other organisms. Whereas 4,4'-diaminodiphenylsulfone has been found to be effective in treating certain infectious and microbial disorders associated with inhibition of folic acid metabolism pathways, comparable potencies have not been observed for the ureido compound. 1-[4-(4'-sulfanilyl)-phenyl]urea, as compared to dapsone and other aminosubstituted diphenyl sulfones has demonstrated the differential effect with the ureidosulfone being far superior to dapsone (.times.10)and other compounds tested and claimed. [U.S. Pat. Nos. 3,689,671 (1972); 3,702,362 (1972); 3,715,375 (1973); 3,775,403 (1973); 3,775,444 (1973); and 3,786,050 (1974)]. Additionally, U.S. Pat. No. 4,338,334 (1982) discloses the use of the substituted diphenyl sulfones resembling the ureido compounds as agents for treating rheumatoid arthritis, muscular dystrophy, or immune complex diseases, but makes no suggestion of the antileishmania actions of said urea derivatives, nor have data been presented to suggest such action by 1-[4-(4'-sulfanilyl)phenyl]urea, and its derivatives, including the novel series of sulfanilyl-2-hydroxyphenyl and sulfanilyl-3-hydroxyphenylureas.
The clinical literature of the diaminodiphenyl sulfones, as compared to the urea derivatives thereof, has not described therapeutically comparable effects for these two classes of compounds.
Dogra described for the first time, the use of unsubstituted diaminodiphenylsulfone as a treatment for leishmaniasis in the clinic [Dogra, et. al., Intl. J. Dermatol, 25:398-400 (1986)] but no follow-up studies of the use of ureido derivatives, in vivo or in vitro appeared. The continuing interest in the diaminosulfones, but not the ureas, is found in the clinical literature [Dogra, Infection,20:189-191 (1992), "Current therapies for treatment of cutaneous leishmaniasis in India", and Dogra, J. "A double blind study on the efficacy of oral dapsone in cutaneous leishmaniasis Trans. R.Soc. Trop. Med. Hyg. 85:212-13 (1991) and no comparable utility of the ureido derivatives of the sulfones is disclosed or even suggested by those skilled in studies of leishmaniasis and/or its causative pathogens of the family Leishmania.